Protein Binding of Lopinavir and Ritonavir During 4 Phases of Pregnancy

Patterson, Kristine B.; Dumond, Julie B.; Prince, Heather A.; Jenkins, Amanda J.; Scarsi, Kimberly K.; Wang, Ruili; Malone, Stephanie; Hudgens, Michael G.; Kashuba, Angela D. M.

doi:10.1097/qai.0b013e31827fd47e

Cited by 37 publications

(41 citation statements)

References 28 publications

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“…Analysis of virologic response in pregnant women receiving 400/100 mg of LPV/r BID demonstrated no association with LPV exposure and no difference compared with responses of nonpregnant subjects, which is consistent with demonstration of LPV plasma trough concentrations above 1 g/ml. The virologic response is also consistent with the demonstrated efficacy in both treatment-naive and treatment-experienced HIV subjects of the original SGC formulation of LPV/r (21,55), which has lower LPV exposure than the tablet formulation.…”

Section: Discussionsupporting

confidence: 64%

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No Need for Lopinavir Dose Adjustment during Pregnancy: a Population Pharmacokinetic and Exposure-Response Analysis in Pregnant and Nonpregnant HIV-Infected Subjects

Salem

Jones

Santini-Oliveira

et al. 2016

Antimicrob Agents Chemother

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Lopinavir-ritonavir is frequently prescribed to HIV-1-infected women during pregnancy. Decreased lopinavir exposure has been reported during pregnancy, but the clinical significance of this reduction is uncertain. This analysis aimed to evaluate the need for lopinavir dose adjustment during pregnancy. We conducted a population pharmacokinetic analysis of lopinavir and ritonavir concentrations collected from 84 pregnant and 595 nonpregnant treatment-naive and -experienced HIV-1-infected subjects enrolled in six clinical studies. Lopinavir-ritonavir doses in the studies ranged between 400/100 and 600/150 mg twice daily. In addition, linear mixed-effect analysis was used to compare the area under the concentration-time curve from 0 to 12 h (AUC 0 -12 ) and concentration prior to dosing (C predose ) in pregnant women and nonpregnant subjects. The relationship between lopinavir exposure and virologic suppression in pregnant women and nonpregnant subjects was evaluated. Population pharmacokinetic analysis estimated 17% higher lopinavir clearance in pregnant women than in nonpregnant subjects. Lopinavir clearance values postpartum were 26.4% and 37.1% lower than in nonpregnant subjects and pregnant women, respectively. As the tablet formulation was estimated to be 20% more bioavailable than the capsule formulation, no statistically significant differences between lopinavir exposure in pregnant women receiving the tablet formulation and nonpregnant subjects receiving the capsule formulation were identified. In the range of lopinavir AUC 0 -12 or C predose values observed in the third trimester, there was no correlation between lopinavir exposure and viral load or proportion of subjects with virologic suppression. Similar efficacy was observed between pregnant women and nonpregnant subjects receiving lopinavir-ritonavir at 400/100 mg twice daily. The pharmacokinetic and pharmacodynamic results support the use of a lopinavir-ritonavir 400/100-mg twice-daily dose during pregnancy.T he use of combination antiretroviral therapy (cART) is recommended in all pregnant women with HIV infection for prevention of perinatal transmission as well as for maternal health. Such use has resulted in a significant reduction of perinatal transmission from 25% to 0 -3.6% (1, 2). Treatment guidelines include the use of protease inhibitors in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) (3-7).Lopinavir (LPV) is a peptidomimetic HIV type 1 (HIV-1) protease inhibitor. When LPV is coadministered with low-dose ritonavir (RTV), which acts as a pharmacokinetic enhancer by blocking the cytochrome P450 3A (CYP3A)-mediated metabolism of LPV, serum levels of LPV are significantly increased, and half-life is prolonged. The high LPV exposures achieved with coformulated lopinavir-ritonavir (LPV/r) have the advantage of providing a pharmacologic barrier to the emergence of HIV-1 viral resistance in patients with wild-type virus, as well as enhanced activity against some forms of drug-resistant HIV-1 (8).Because of the potency of ...

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Section: Discussionsupporting

confidence: 64%

“…Study 3 was a two-center, open-label study that compared the pharmacokinetics of the LPV/r tablet at 400/100 mg BID and 500/125 mg BID during the third trimester of pregnancy (21). The 500/125-mg dose was achieved by adding a half-strength tablet of LPV/r of 100/25-mg to two 200/50-mg tablets.…”

Section: Methodsmentioning

confidence: 99%

No Need for Lopinavir Dose Adjustment during Pregnancy: a Population Pharmacokinetic and Exposure-Response Analysis in Pregnant and Nonpregnant HIV-Infected Subjects

Salem

Jones

Santini-Oliveira

et al. 2016

Antimicrob Agents Chemother

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“…The unbound fraction (F u ) was estimated by using the trough concentration; in pregnant women, the median F u was 1.5%. This value is comparable to those previously described (0.84 to 2%) (12,14,23,34). Moreover, bootstrap, VPC, and NPDE procedures allowed a good evaluation of these two models.…”

Section: Discussionsupporting

confidence: 75%

“…These values for plasma protein concentrations come from nonpublished data of our lab and reported values (23,34).…”

Section: Population Pharmacokinetic Analysis (I) Model Developmentmentioning

confidence: 99%

Population Approach To Analyze the Pharmacokinetics of Free and Total Lopinavir in HIV-Infected Pregnant Women and Consequences for Dose Adjustment

Fauchet

Tréluyer

Illamola

et al. 2015

Antimicrob Agents Chemother

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The aims of this study were to describe the unbound and total lopinavir (LPV) pharmacokinetics in pregnant women in order to evaluate if a dosing adjustment is necessary during pregnancy. Lopinavir placental transfer is described, and several genetic covariates were tested to explain its variability. A total of 400 maternal, 79 cord blood, and 48 amniotic fluid samples were collected from 208 women for LPV concentration determinations and pharmacokinetics analysis. Among the maternal LPV concentrations, 79 samples were also used to measure the unbound LPV concentrations. Population pharmacokinetics models were developed by using NONMEM software. Two models were developed to describe (i) unbound and total LPV pharmacokinetics and (ii) LPV placental transfer. The pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. A pregnancy effect was found on maternal clearance (39% increase), whereas the treatment group (monotherapy versus triple therapy) or the genetic polymorphisms did not explain the pharmacokinetics or placental transfer of LPV. Efficient unbound LPV concentrations in nonpregnant women were similar to those measured during the third trimester of pregnancy. Our study showed a 39% increase of maternal total LPV clearance during pregnancy, whereas unbound LPV concentrations were similar to those simulated in nonpregnant women. The genetic polymorphisms selected did not influence the LPV pharmacokinetics or placental transfer. Thus, we suggest that the LPV dosage should not be increased during pregnancy. N ew recommendations were published by the World Health Organization (WHO) in 2013 for use of antiretroviral drugs for treating and preventing HIV infection (1). These recommendations suggested simplification and harmonization of the firstline therapy in order to improve health outcomes and facilitate adherence and drug procurement (1). A new combination regimen has been suggested for all HIV-infected adults, including pregnant and breastfeeding women. Two nucleoside reverse transcriptase inhibitors (NRTIs) and one nonnucleoside reverse transcriptase inhibitor are recommended as a first-line regimen to treat infected pregnant women or to prevent mother-to-child transmission (MTCT). However, the use of NRTIs during pregnancy has been recently debated. Indeed, NRTIs cross the placenta with an affinity for both mitochondrial and nuclear human DNA (2, 3). The use of NRTIs in large cohorts of neonates and children has been associated with toxicities (including mitochondrial dysfunction and neurological disease) (4, 5). Moreover, genotoxic biomarkers were identified in neonates exposed to zidovudine (ZDV) alone or in combination with lamivudine (3TC) (6, 7). The long-term toxicities of NRTIs remain unknown, but they raise concern about use of these drugs during pregnancy.Considering the possible NRTI toxicities during pregnancy, the ANRS 135 PRIMEVA study compared a triple-therapy regimen containing NRTIs versus LPV monotherapy. The study also compared the effi...

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“…[ 54] Studies have shown that total LPV concentrations are significantly reduced in pregnancy, but unbound LPV concentrations are not affected. [55] Therefore, dose adjustment of LPV/r is not recommended in pregnancy. However, once-daily dosing of LPV/r should not be used in pregnancy.…”

Section: Nnrti and Pi Choice In Pregnancymentioning

confidence: 99%

Adult antiretroviral therapy guidelines 2014

Meintjes¹

2014

South. Afr. j. HIV med.

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Correspondence: Southern African HIV Clinicians Society (sahivsoc@sahivsoc.org)Disclaimer: Specific recommendations provided here are intended only as a guide to clinical management, based on expert consensus and best current evidence. Treatment decisions for patients should be made by their responsible clinicians, with due consideration for individual circumstances. The most current version of this document should always be consulted.These guidelines are intended as an update to those published in the Southern African Journal of HIV Medicine in 2012. Since the release of the previous guidelines, the scale-up of antiretroviral therapy (ART) in southern Africa has continued. Cohort studies from the region show excellent clinical outcomes; however, ART is still being initiated late (in advanced disease) in some patients, resulting in relatively high early mortality rates. New data on antiretroviral drugs have become available. Although currently few, there are patients in the region who are failing protease-inhibitor-based second-line regimens. To address this, guidelines on third-line therapy have been expanded.

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Protein Binding of Lopinavir and Ritonavir During 4 Phases of Pregnancy

Cited by 37 publications

References 28 publications

No Need for Lopinavir Dose Adjustment during Pregnancy: a Population Pharmacokinetic and Exposure-Response Analysis in Pregnant and Nonpregnant HIV-Infected Subjects

No Need for Lopinavir Dose Adjustment during Pregnancy: a Population Pharmacokinetic and Exposure-Response Analysis in Pregnant and Nonpregnant HIV-Infected Subjects

Population Approach To Analyze the Pharmacokinetics of Free and Total Lopinavir in HIV-Infected Pregnant Women and Consequences for Dose Adjustment

Adult antiretroviral therapy guidelines 2014

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